1. Field of the Invention
The present invention relates to acid addition salts of 2-acetoxy-5-(xcex1-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (preferably the hydrochloride or maleate) which exhibit excellent oral absorption, metabolization into the active compound, and activity in inhibition of platelet aggregation, and are useful as therapeutic or prophylactic agents for thrombus formation-induced or embolization-induced diseases.
2. Background Information
In EP-542411 (Japanese Patent Application Publication No. Hei 6-411239) it is described that 2-acetoxy-5-(xcex1-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine and derivatives thereof, which are antagonists of receptors of adenosine diphosphate (hereinafter referred to as xe2x80x9cADPxe2x80x9d), exhibit excellent activity in inhibition of platelet aggregation and are useful as antithrombotic or antiembolic agents.
For many years the present inventors have earnestly studied the pharmacological activity of various hydropyridine derivatives in order to discover compounds having excellent activity in inhibition of platelet aggregation. The present inventors have found that acid addition salts of 2-acetoxy-5-(xcex1-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (preferably the hydrochloride or maleate) exhibit excellent oral absorption, metabolization into the active compound, activity in inhibition of platelet aggregation, low toxicity, and excellent storage and handling stability, and are useful as medicaments (preferably useful as therapeutic or prophylactic agents (preferably therapeutic agents)) for thrombus formation-induced or embolization-induced diseases (preferably thrombosis or embolism).
The present invention provides acid addition salts of 2-acetoxy-5-(xcex1-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (preferably the hydrochloride or maleate), which exhibit excellent activity in inhibition of platelet aggregation; processes for the preparation thereof; and medicaments containing them which are useful as therapeutic or prophylactic agents (preferably therapeutic) for thrombus formation-induced or embolization-induced diseases, and are preferably useful as therapeutic or prophylactic agents (preferably therapeutic agents) for thrombosis or embolism.
The present invention relates to acid addition salts of 2-acetoxy-5-(xcex1-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (hydrochloride or maleate) and relates to medicaments containing acid addition salts of 2-acetoxy-5-(xcex1-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (hydrochloride or maleate) as an active ingredient.
The acid moiety of acid addition salts of 2-acetoxy-5-(xcex1-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine is, for example, an inorganic acid such as sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid; or an organic acid such as trifluoroacetic acid, maleic acid, methanesulfonic acid, p-toluenesulfonic acid, and preferably hydrochloric acid or maleic acid.
2-Acetoxy-5-(xcex1-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride of the present invention has the following formula: 
2-Acetoxy-5-(xcex1-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine maleate has the following formula: 
Acid addition salts of 2-acetoxy-5-(xcex1-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine have an asymmetric carbon in their molecule and in each compound two isomers having R and S configurations can exist. The present invention encompasses the individual isomers and mixtures of these isomers in optional proportions. An optically active isomer of acid addition salts of 2-acetoxy-5-(xcex1-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine of the present invention can be prepared using an optically active starting material or is isolated from a racemic mixture of synthetically prepared acid addition salts of 2-acetoxy-5-(xcex1-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine by a conventional optical resolution.
In some cases, when acid addition salts of 2-acetoxy-5-(xcex1-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine are allowed to stand in contact with the atmosphere or are recrystallized, they may absorb water or may take up water to form a hydrate. The present invention encompasses these hydrates.
Acid addition salts of 2-acetoxy-5-(xcex1-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine are prepared in the presence or absence of an inert solvent (preferably in an inert solvent) by addition of 2-acetoxy-5-(xcex1-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, which is synthesized by a method described in EP-542411, to an acid (preferably hydrochloric acid, hydrogen chloride (gas), or maleic acid; more preferably concentrated hydrochloric acid or maleic acid; most preferably concentrated hydrochloric acid); or in the presence or absence of an inert solvent (preferably in an inert solvent) by dropwise addition or addition of an acid (preferably hydrochloric acid, hydrogen chloride (gas), or maleic acid; more preferably concentrated hydrochloric acid or maleic acid; most preferably concentrated hydrochloric acid) at one or more times to 2-acetoxy-5-(xcex1-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine. In this procedure, if necessary, seed crystals of said salt can be added.
The solvent used in the above reaction is not particularly restricted provided that it has no adverse effect on the reaction and it can dissolve the starting material to some extent. Examples of such solvents include aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; ether derivatives such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethyleneglycol)dimethyl ether; ketone derivatives such as acetone, methyl ethyl ketone or diethyl ketone; ester derivatives such as ethyl acetate, propyl acetate or butyl acetate; carboxylic acid derivatives such as acetic acid or propionic acid; or nitrile derivatives such as acetonitrile or propionitrile. For the preparation of the hydrochloride, the preferred solvents are ether derivatives, ketone derivatives, ester derivatives, carboxylic acid derivatives or nitrile derivatives; more preferred solvents are tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, ethyl acetate, acetic acid or acetonitrile; still more preferred solvents are tetrahydrofuran, dioxane, acetic acid or acetone. Acetone is the most preferred. On the other hand for the preparation of the maleate, the preferred solvents are ether derivatives, ketone derivatives, ester derivatives or nitrile derivatives; more preferred solvents are tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, ethyl acetate, or acetonitrile; still more preferred solvents are tetrahydrofuran, dioxane or acetone. Acetone is the most preferred.
The reaction temperature will vary depending on the reagent, the solvent and the like, and usually is from xe2x88x9220xc2x0 C. to 100xc2x0 C., preferably from 0xc2x0 C. to 70xc2x0 C. With respect to the hydrochloride, the reaction temperature is preferably from 30xc2x0 C. to 60xc2x0 C. and more preferably from 40xc2x0 C. to 55xc2x0 C.
The reaction time will vary depending on the reagent, the solvent, the reaction temperature and the like, and usually is from 5 minutes to 10 hours, preferably 10 minutes to 5 hours.
With respect to the preparation of the maleate, the reaction is preferably carried out by addition of 2-acetoxy-5-(xcex1-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine to a solution of maleic acid in acetone between 0 and 70xc2x0 C. followed by allowing to stand at said temperature for 1 hour to 3 hours.
With respect to the preparation of the hydrochloride, the reaction is preferably carried out by addition or dropwise addition of the required amount of concentrated hydrochloric acid (usually equimolar with respect to the thienopyridine derivative) to a solution of 2-acetoxy-5-(xcex1-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine in acetone between 0xc2x0 C. and 70xc2x0 C. (preferably between 35 and 60xc2x0 C.) followed by allowing to stand at said temperature for 30 minutes to 3 hours.
More preferably the reaction is carried out by dropwise addition of half of the required amount of concentrated hydrochloric acid (usually equimolar with respect to the thienopyridine derivative) to a solution of the thienopyridine derivative in acetone between 35xc2x0 C. and 60xc2x0 C. (preferably between 40 and 55xc2x0 C.) over from 2 minutes to 10 minutes, with addition of seed crystals of said salt if necessary, followed by allowing to stand at said temperature for 30 minutes to 2 hours; and then by further dropwise addition of the remaining required amount of concentrated hydrochloric acid to the reaction mixture over from 30 minutes to 2 hours followed by allowing to stand at said temperature for 1 hour to 3 hours.
After the reaction, the acid addition salts of 2-acetoxy-5-(xcex1-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine can be isolated from the reaction mixture by conventional methods. For example, after the reaction, the resulting crystals are isolated by filtration to afford the desired product or the solvent of the reaction mixture is evaporated to afford the desired product. The product, if necessary, can be purified by recrystallization, reprecipitation or chromatography.
The acid addition salts of 2-acetoxy-5-(xcex1-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine of the present invention exhibit excellent oral absorption, metabolism into the active compound, and activity in inhibition of platelet aggregation, low toxicity, and further excellent storage and handling stability, therefore, they are useful as prophylactic or therapeutic agents (preferably therapeutic agents) for thrombus formation-induced or embolization-induced diseases; more preferably prophylactic or therapeutic agents (preferably therapeutic agents) for thrombosis or embolism. The medicaments described above are preferably for a warm blooded animal, more preferably a human.
When the acid addition salts of 2-acetoxy-5-(xcex1-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine of the present invention are used as therapeutic or prophylactic agents for the diseases as described above, they can be administered alone or as a mixture with pharmaceutically acceptable excipients, diluents and the like, in various dosage forms such as tablets, capsules, granules, powders, syrups or the like for oral administration; and injections, suppositories or the like for parenteral administration.
Each of the above formulations can be prepared by well-known methods using additives (i.e., pharmaceutically acceptable carriers) for the formulation such as excipients, lubricants, binders, disintegrants, emulsifiers, stabilizers, corrigents, and diluents.
Examples of excipients include organic excipients, for example sugar derivatives such as lactose, sucrose, glucose, mannitol or sorbitol; starch derivatives such as corn starch, potato starch, xcex1-starch or dextrin; cellulose derivatives such as crystalline cellulose; acacia; dextran; pullulan; and inorganic excipients; for example silicate derivatives such as light silicic acid anhydride, synthetic aluminum silicate, calcium silicate, or magnesium aluminate metasilicate; phosphate derivatives such as calcium hydrogenphosphate; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate, or the like.
Examples of lubricants include stearic acid; metal stearate derivatives such as calcium stearate or magnesium stearate; talc; waxes such as beeswax or spermaceti; boric acid; adipic acid; sulfate derivatives such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL-Leucine; lauryl sulfate derivatives such as sodium lauryl sulfate or magnesium lauryl sulfate; silicic acid derivatives such as silicic anhydride or silicic acid hydrate; and starch derivatives as described in the excipients above.
Examples of binders include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol (trade name) or excipients as described in the excipients above.
Examples of disintegrants include cellulose derivatives such as lower-substituted hydroxypropylcellulose, carboxymethylcellulose, calcium carboxymethylcellulose or internally cross-linked sodium carboxymethylcellulose; chemically modified starch or cellulose derivatives such as carboxymethylstarch or sodium carboxymethylstarch; cross-linked polyvinylpyrrolidine; and starch derivatives as described above.
Examples of emulsifiers include colloidal clay such as bentonite or veegum; metal hydroxides such as magnesium hydroxide or aluminum hydroxide; anionic surfactants such as sodium lauryl sulfate or calcium stearate; cationic surfactants such as benzalkonium chloride; non-ionic surfactants such as polyoxyethylene alkyl ether, polyoxyethyene sorbitan esters of fatty acids or sucrose esters of fatty acids.
Examples of stabilizers include para-hydroxybenzoic acid ester derivatives such as methylparaben or propylparaben; alcohol derivatives such as chlorobutanol, benzyl alcohol or phenethyl alcohol; benzalkonium chloride; phenol derivatives such as phenol or cresol; thimerosal; dehydroacetic acid or sorbic acid.
Examples of corrigents include sweeteners, souring agents, flavorings or the like which are conventionally used.
The specific dose of a compound of the present invention will be varied according to the severity of the patient""s symptoms, age and the like. For oral administration the quantity of active ingredient in a unit dosage may be in the range of 0.1 mg (preferably 1 mg) to 1000 mg (preferably 500 mg). A unit dose for intravenous administration may be in the range of 0.01 mg (preferably 0.1 mg) to 500 mg (preferably 250 mg) of a compound of the present invention.
The unit dose may be administered to a human adult from 1 to 7 times per a day for a period of from 1 to 7 days depending on the severity of the patient""s symptoms.